Keratoconus (KG) is a non-inflammatory thinning disorder of the cornea with an incidence of approximately 1/2000 in the general population. As the etiology of KG is still unknown, there have been no effective therapeutic measures for the treatment of KC other than contact lenses and cornea transplantation. Association with rare genetic syndromes, observation of apparent autosomal dominant pedigrees, and results from complex segregation analysis all suggest that the genetic factors may play an important role in the susceptibility of KC. The overall goal of this application is to identify susceptibility genes for KC by (1) more clearly refining our topographic criteria for detecting subclinical KC (KC 'suspects') through longitudinal topographic analysis of our existing cohort of patients and their relatives, (2) recruiting additional KC families suitable for nonparametric linkage analysis, and (3) performing a two stage genome-wide screen with model free linkage and association methods. Specifically, all existing study subjects (-2000) will undergo ocular evaluation and videokeratography over the next 5 years to observe longitudinal and clinical topographic changes in order to examine the relationship of videokeratography variables to biomicroscopic indicators of disease status and to develop more refined criteria for 'mildly affected' (subclinical) KC family members (Aim 1). We will recruit an additional 195 keratoconus families with at least 5 family members available to be phenotyped to provide an independent set of families to confirm the linkage findings from the initial scan (Aim 2). We will employ a two stage genomewide screen approach with two sets of families (initial panel and confirmatory panel) and two levels of markers (initial screen markers and fine mapping markers) to identify chromosomal regions linked to KC. Quantitative videokeratographic indices will be used as primary phenotypes in linkage analysis. After the linked regions are confirmed in the second sample, association studies will be carried out for candidate genes in the linked regions to identify specific susceptibility alleles. Identifying genes contributing to the pathogenesis of KG may provide insights into devising medical therapy to arrest its progression and prevent the need for multiple contact lens changes and/or cornea transplantation in select hiah risk individuals.